1. Field of the Invention
The present invention relates to reduction of apoptosis in brain tissue and cells, and more particularly, to the use of miR-23a-3p and/or miR-27a-3p mimics as therapeutic agents to reduce neuronal apoptosis in injured brain tissue and cells.
2. Description of the Related Art
Traumatic brain injury (TBI) occurs when an outside force impacts the brain and such injury is usually due to a brief event occurring in less than a second. Such an injury may be due to a vehicular accident, a violent act or a sports-related injury. The main problem associated with TBI is neuronal cell death and the outcome of TBI ranges from complete recovery to permanent disability, and sometimes death. Also, TBI initiates secondary cell death mechanisms that contribute to tissue damage and neurological dysfunction (Stoica and Faden, 2010).
Neuronal cell death is also found in many other human neurological disorders including Alzheimer's, Parkinson's and Huntington's disease, stroke and amyotrophic lateral sclerosis (ALS). Neurons in the brain are interconnected and if the functional connections are separated the result is impaired brain function. Clearly, understanding how to regulate apoptosis could be the first step to treating these brain injuries or diseases.
Brain trauma due to any of the other above described diseases or injuries is usually associated with regional apoptosis. Apoptotic cell death is a highly regulated cellular process in which a cell is instructed to shut itself down and is eliminated. Apoptosis initiates a cascade of intracellular events to effect cell death and particularly suppresses the expression of expression of anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) proteins.
The Bcl-2 family of proteins includes both pro- and anti-apoptotic members. Full members of the Bcl-2 family share homology in four conserved domains designated BHI, BH2, BH3 and BH4. BH3 includes proteins, such as, Puma, Noxa, Bid and Bim all of which promote neuronal cell death by binding and inactivating anti-apoptotic Bcl-2 family members, and by direct activation of pro-apoptotic multi-BH domain proteins (Bax and Bak), which ultimately cause release of pro-apoptotic molecules from mitochondria (cytochrome c and apoptosis inducing factor (AIF)) (Lomonosova and Chinnadurai, 2008; Shamas-Din et al., 2011). BH3-only proteins have been implicated in neuronal cell death after CNS injury, including TBI (Engel et al., 2011). The mechanisms responsible for up-regulation and activation of BH3-only proteins include both p53 dependent and independent mechanisms (Jeffers et al., 2003; Yakovlev et al., 2004).
MicroRNAs (miRs) are a broad class of small non-coding RNAs that control diverse biological processes including major signaling pathways by regulating the expression of complementary target mRNAs. miRs are short (20-23 nucleotide) noncoding RNAs that negatively regulate gene expression at the post-transcriptional level by binding to the 3′-untranslated region (UTR) of target mRNAs, leading to their degradation and/or translational inhibition (Griffiths-Jones et al., 2006). Recent studies indicate that miRs are involved in the pathophysiology of brain seizures, ischemia and trauma (Lei et al., 2009; Redell et al., 2009 ; Liu et al., 2010; Ziu et al., 2011). miRs modulate neuronal cell death pathways (Jimenez-Mateos and Henshall, 2013), but few have been directly evaluated in the context of TBI or other brain injury (Siegel et al., 2011; Selvamani et al., 2012), and thus, their mechanisms of action in this regard remains largely unknown.
miR-23a may play an important role in regulation of apoptosis in human ovarian granulosa cells (Yang et al., 2012) and human keratinocytes (Guo et al., 2013), as well as in sex-dependent regulation of X-linked inhibitor of apoptosis (XIAP) following cerebral ischemia (Siegel et al., 2011). Previous studies that examined miR modulation after TBI have been largely descriptive, and have focused only tangentially on the miR-23a˜27a˜24-2 cluster and encoding primary miRNAs transcript (pri-miRNA) (Lei et al., 2009; Truettner et al., 2011; Hu et al., 2012).
As such, it would be advantageous to identify new agents and mechanisms that can reduce neuronal apoptosis thereby providing new approaches for treating neurodegenerative disorders or TBI.